The objective of the proposed research is to define the molecular mechanism of action of alpha-1-antitrypsin (AAT). AAT is a protein in human serum which inhibits many enzymes. Individuals who have a genetically determined severe deficiency of the protein in serum, usually develop emphysema at an early age. Specific goals include: 1. Elucidation of the function of enzymes inhibited by AAT, and consequently the mechanism of emphysema production in patients with severe AAT deficiency. 2. Comprehension of the mechanism of disease production in patients with other forms of emphysema, if there are common features of the disease processes. 3. Availability of information which may permit the designing of drugs which could replace the function of AAT in patients with the deficiency. The goals will be approached by studying the interaction of purified AAT in vitro with purified enzymes under specified conditions and with various specific modifications of the AAT or of the enzymes. BIBLIOGRAPHIC REFERENCES: Lo, T.N., Cohen, A.B., and James, H.L.: The Interaction of alpha-1-antitrypsin with soluble and sepharose-bound elastase. Biochim. Biophys. Acta. 453: 344-346, 1976. Glaser, C.B., Karic, L. and Cohen, A.B.: Low pH stability of alpha-1-antitrypsin. Biochim. Biophys. Acta. 491: 325-330, 1977.